In this second resubmission we have addressed the concerns and comments of reviewers. The proposal now includes two additional experiments designed to measure the tonic pool of dopamine in ADHD patients and healthy volunteers. Both, tonic and phasic release will now be measured in the same volunteers. This exploratory study will use molecular imaging to examine a hypothesis concerning dysregulation of dopamine neurotransmission in ADHD. The nature of dysregulation of the dopamine system in ADHD is unclear because studies have suggested either hyperactivity or hypoactivity of the system. It appears that the studies that have examined the tonic pool of dopamine have found hypoactivity, while those that have investigated the phasic pool have reported hyperactive dopamine system. It has been hypothesized that, in ADHD there is a reduction of the tonic pool. This triggers excessive phasic release, which dysregulates activities of the central executive and reward systems, leading to ADHD symptoms. If assumptions of this hypothesis are valid, most of the contradictory data on dopaminergic activity in ADHD could be reconciled. Studies have suggested that the tonic pool is reduced, but the validity of assumption concerning the phasic release has not yet been examined because of the lack of a reliable method to measure dopamine released during a task performance. We have recently demonstrated that the task-induced release of striatal dopamine can be reliably detected using a molecular imaging technique. Since striatal dopamine is an important modulator of the central executive and reward systems (that are dysregulated in ADHD), this technique provides an excellent tool to test the hypothesis concerning the phasic release. We propose to examine whether the phasic release of striatal dopamine is enhanced in ADHD during performance of tasks that require response inhibition or sustained attention. The phasic release during response inhibition will be measured in healthy control volunteers (Experiment 1) and predominantly hyperactive-impulsive subtype of ADHD patients (Experiment 2) during performance of Eriksen's flanker task. The release during sustained attention will be studied in healthy volunteers (Experiment 3) and predominantly inattentive subtype of ADHD patients (Experiment 4), using a rapid visual information processing task. In addition, using a molecular imaging technique, the tonic pool of dopamine will be measured in the same ADHD patients (Experiment 5) and healthy volunteers (Experiment 6) who will participate in Experiments 1-4. These experiments will evaluate whether the tonic pool is reduced in ADHD. The proposed study will examine an important hypothesis concerning pathophysiology of ADHD and will help us understand whether the dopamine system is differentially dysregulated in the two subtypes of ADHD. The results will provide information that could be used to develop novel diagnostic and therapeutic strategies. PUBLIC HEALTH RELEVANCE: In this study we propose to use a dynamic molecular imaging technique to examine a hypothesis concerning dysregulation of dopamine neurotransmission in attention deficit hyperactivity disorder (ADHD). The experiments will compare the baseline and task-induced release of dopamine in ADHD patients and healthy control volunteers. These experiments will provide information that could be used to develop novel diagnostic and therapeutic strategies.